Enol derivatives of cyclopentano phenanthrene compounds and process of making same



puma has, 1 41' 2,248,438

ENOL DERIVATIVES F CYCLOPEN'I'ANO PHENANTHRENE COMPOUNDS AND PROC- ESSOF MAKING SAME Leopold Ruzicka, Zurich, and Werner Fischer,

Basel, Switzerland, assigno 's, by mesne assignments, to CiliaPharmaceutical Products, Incorporated, Summit, N. J., a corporation ofNew Jersey No Drawing. Application May 12, 1937, Serial No. 142,278. InSwitzerland May 18, 1936 l'l'claims. (Cl. zen-397.4)

This invention relates to the manufacture of Example 1 new enolderivatives of vcyclopentano phenanthrene compounds, consisting intreating a ken f lparts of A -cholestenone (3) of the cyclopentanophenanthrene compound with an m acyiating agent in presence or absenceof an acid 5 CH: CH: binding agent. 4

Suitable acylating agents are, for example, or- I ganic or inorganicacid halides or anhydrides. When an organic acid halide is used anorganic ester of the enol or its halide, or both the ester 19 and thehalide, can be produced. The ester is advantageously made in an openvessel so that the hydrogen halide which is formed may escape; ;hehalide is chiefly obtained when the reaction JCClils in a closed vesselThus for example by mixed with 8 parts of enzoyl chloride in 50 ;he Iaction of benzoyl chloride on A' -cholesparts of pure benzme (boflmgpoint 100 and ;enone-(3), either the benzoic acid ester of the l i zl g23 252: g i si li thi b e ie sr ir i hg z yl mo] of Formula I or itschloride of Formula II is chloride in a vacuum, the product is heated onthe noduced' water bath with /2N-caustic soda solution, then dilutedwith water and extracted with ether.

The ethereal solution is washed with caustic soda solution and water anddried over sodium sulfate. The enol-benzoate of cholestenone is crys- 25tallized in part by evaporating the solution; it is /V stirred with alittle acetone to form a magma which is then' filtered and washed withcold acep tone on the filter until the washings are colorless.

There are thus obtained 9.1 parts of the colorless ester of the farmulaI on, on,

CH: C

HI l I M. V N

V I C6HI.c0.0'\\/\/ Cl g 40 of melting point1l6-117" C. From the motherliquor a further quantity may be recovered.

With tetramtromethane, the enol-ester-yields an n intensely redcolor.

CaHn

The reaction may be conducted in absence of The new enol derivativeshave therapcutical a solvent, for example by heating cholestenonepplication or they may serve as intermediate with 'benzoyl chloride toISO-170 C. For the roducts for making-therapeutically active compurposeof binding the hydrochloric acid proounds. duced, there may be added,for example, a ter- The' following examples illustrate the inventiarybase such a pyridine. on. the parts being byweight: L In. like mannerone can obtain the isomeric benzoic acid enol-ester from A-=-cholestenone- (3) according to the following equation:

and 50 parts of benzoyl chloride are heated in a bomb'tube for 22 hoursat 100 C. vAfter distilling the excess of benzoyl chloride in a. vacuum,

the oily product is heated with ygN-caustic soda solution for 30-minuteson the water bath: it is then diluted with water and extracted withether. The ethereal solution is shaken with caustic soda solution andwater, and dried over sodium sulfate. The oily product crystallizes onaddition of a little acetone: 9 parts oi the chloride of theenol of theformula CH: CH!

--COHl1 V are obtained. In pure condition the compound melts at61.5-62.5 C. This new chloride becomes intensely yellow-brown onaddition of tetranltromethane.

Example 3 2 parts of cholestanone of the formula,

cm on:

and 10 parts of acetyl chloride are heated together in a bomb tube for16 hours at 100' C. The contents oi the tube are then poured into waterand the product of the reaction is extracted from the aqueous liquid bymeans of ether; the ethereal solution is washed with caustic sodasolution and water and dried over sodium sulfate. The oil obtained byevaporating the solvent yields no semicarbazone and crystallizes afterlong standing. The simple unsaturated chloride thus obtained of theformula on, on,

may be recrystallized from acetone, a mixture or alcohol and hexane or amixture of alcohol and benzene. It melts at 81 C. and yields withtertanltromethane a pronounced yellow color.

' Example 4 10 parts of A -androstene-dione- (3,17) of the formula cm omare mixed with 16.5 parts of benzoyl chloride in 400 parts of purebenzine (boiling point C.) and the mixture is boiled for 40 hours. Oncooling to room temperature, the new ester of the .iormula CH: CH:

separates in the form of beautifully formed crystale. It is filtered andwashed with cold benzine. Thetcompound sinters at 168 C. and melts withdecomposition between176 and 180 C. The line. colorless needles yieldwith tetranitmmethane a pronouncedyellow-brown color.

The yield of the enol-ester amounts to about '10 per cent. and analysisshows that it is a monoester of androstene -dione enolized int-position.

Example 5 Accordingto the procedure described in Example 1 there areobtained from 20 parts of cholestanone oi the formula CH: CH:

and 16 parts of benzoyl chloride 21.5 parts or the enol-benzoate ofcholestanone of the formula can which after recrystallization fromacetone melts at 121428 C.

GiKaCOD Example 6 I Example 8 .n mixtureof 0.2 part of A-andmstene-dione- I A mixture of 0.1 part of testosterone of the (3.17)of theformula a formula CHI CH! CH: CH] 5 3.5 parts of acetic anhydrideand 0.2 part of 7 parts of acetic anhydflde a part or freslffly freshlyfused potassium acetate is heated to boilfused potass um acetate isheated honing 15 mg for about 42 hours and the reaction mixture hoursthecontents?! the vessel are is then poured into water and the product ismm'ed into water and the product is extracted with ether. After theethereal extract tl'med ether. The ethereal solution is has been dilutesodium carbonate washed with dilute sodium carbonate somfim' solution,dilute caustic alkali solution and water then with caustic alkalisolution and with water, it is dried by means of sodium sulfate and theby means of sodium sulfate and solvent solvent is evaporated. Theresidue of the dis- 18 then evammted- There remains a mixture tillationis stirred with acetone and filtered. The.

which partly crystallizes and can be filtered on the addition of a smallquantity of methanol. fg gg gfl iwffihz gi giz fie fie of The product isthen dissolved in methanol and the fraction which first separates. beingnot quite 1 pure, is removed. After concentrating the solu- 00 CH tionand cooling it for a long time at --.10 C.

beautiful needles of the enol-monoacetate of n -androstene-dione-(ml'llof the formula q/ cmcoo V CH; C H:

p I melts at 150-151 0. and can'be recrystallized from alcohol. It givesa pronounced brown color with tetranitromethane. In a similar manner byheating cholestenone V withacetic anhydride in presence or absence of asolvent until the reaction is finished there is separate. Th product,canbe recrystalliied from obtained the enoi-acetate of cholestenone ofmethanol; it melts at 127-129 C. and gives a melting point 78 C. Itgives a brown color with ye11w br0wn c0101- m t t it t tetranitromethaneand can be recrystallized from Z a mixture of acetone and alcohol. Exam?8 7 Instead of acetic anhydride there may be used Amixture of 0.256 partof testosterone-benzoatean acetic acid halide such as acetyl chloridecrf th formula acetyl bromide. It is also posslble to use as the CH3 CH3acylating agent a ketene such as ketene itself.

, I Example 9 A mixture of 0.2 part of testosterone-propionate l of theformula /W/ V CH5 CH:

0.00-CHLCHI I 2.3 eat. of benzoyl chloride and 12.5 parts of benzlne isheated to boiling for about 44 hours.

After removing the benzine and benzoyl chloride 0- p by filtering theenol-benzoate of testosterone-1 V benzoate of the formula 0.4 part ofanhydrous sodium acetate and '7 parts I of acetic anhydride is heated toboiling for 41 CH3 CH3 hours and the reaction mixture is worked up in lthe manner indicated in the foregoing examples. -o.00.cri There isobtained the 3-enol-acetate of testosterone-17-propionate of theformulaCH: CH!

0.0C.CH|.CH| CsH|-C0.0x v I I crystallizes; it can be obtained pure byrubbing with acetone and melts at 183-184" C. with decm 00 Ocompositioia- 76 which melts at 140-141" C. and gives a brown color withtetranitromethane.

In a similar manner the 3-enol-propionate of testosterone-I'l-acetatecan be obtained from testosterone-acetate. After recrystallization frommethanol it melts at 139.5-141 C. and produces a strong melting pointdepression both with testosterone-i'T-acetate and also withtestosterone-3-enolacetate-i'l-propionate.

Example 10 A mixture of 0.1- part of testosterone of the formula CH3 CH3(or testosterone-17-propionate) 0.2 part of sodium propionate and 4parts of propionic anhydride is heated to boiling in a refluxapparatusfor about 5 hours. By working up the reaction mixture in the matterindicated in Example 8 there is obtained the 3-enol-propionate oftestosterone-l'l-propionate of the formula CH: CH:

which melts at 125-127 C. It gives a brown color with tetranitromethaneand a mixture with testosterone-1'7-propionate shows a. depression inmelting P int.

In an analogous manner there can also be prepared normal or mixeddiesters of testosterone with other acids, for example formic acicl,-

n-butyric acid, iso-butyric acid, valeric acid or palmltic acid.

Corresponding enol-esters can be obtained for example fromandrostane-dione-(3.17), androstane-ol-(1'7) -one- (3), A -chloestenone,A androstene-ol-(17) one- (3) or derivatives thereof.

Example 11 A mixture of 0.1 part of progesterone of the formula CH: CH:

0.2 part of anhydrous sodium acetate and 3.5 parts of acetic anhydrideis heated to boiling for 40 hours. By working up the reaction mixture inthe manner described in the foregoing examples there is obtained the3-enol-acetate f-progresterone of the formula CH! CH! CH which melts at135-1365 C. and gives a brown color with tetranitromethane.

Example 12 A mixture of 0.1 part of progesterone of the formula v 0.2part of anhydrous sodium propionate and 5 parts of propionic anhydrideis heated to boiling in a reflux apparatus for 5 hours. The3-enolpropionate of progesterone of the formula CH CH: CE

thus obtained is recrystallized from methanol and melts at 134-136 C.With tetranitro methane it gives an intense brown color and a mixturewith progesterone shows a depression in melting point.

In a similar manner other enol-esters of progesterone can be prepared,for example the butyrates, valerates, stearate or benzoate.

In an analogous manner also compounds of the series of the hormonesof.the suprarenal cortex, for example the cortical hormone itself,21-oxyprogesterone and esters thereof, can be converted into their enolderivatives such as acetates, propionates. acetate-propionates and Aandrostene dione, 1

or W

with an acylating agent at a-temperature of at least about 100 C. for asuiiicient time to form an enol derivative which is acylated at theenolic hydroxy group.

3. Process for the manufacture of new enol derivatives of3-keto-cyclopentano-10, 13-dimethyl-phenanthrene, comprising heating acompound of the formula wherein R is a member of the group consisting ofand with an aliphatic acylating agent at a temperature of at least about100 C. for a sumcient time to form an enol derivative which is acylatedat the enolic hydroxy group.

4. Process for the manufacture of new enol derivatives ofB-keto-cyclopentano-iO. 13-diniethyl-phenanthrene, comprising heating acompound of the formula CH; CH!

and

III

with an aliphatic acid anhydride at a temperature of at least about .100C. for a sumcient time to form an enol derivative which'is acylated atthe enolic hydroxy group.

5. Process for the manufacture of new enol derivatives of3-keto-cyc1opentano-10, iii-dimenthyl-phenanthren'e. comprising heatinga compound of the formula wherein R is a member of the group consistingof o-acyl and with an aliphatic acid anhydride in the presence of ananhydrous salt of such an acidat a temperature of at least about 100 C.for a suflicient time to form an enol derivative which is acylated atthe enolic hydroxy group.

6. Process for the manufacture of the enol propionate oftestosterone-17-propionate, comprising treating a member of the groupconsisting of testosterone and testosterone-l'Z-propionate withpropionic acid anhydride in the 'presence of a propionic acid salt at atemperature of at least about C. for a sumcient time to form an enolderivative which is acylated at the enolic hydroxy group.

7. Process for the manufacture of new enol derivatives of3-keto-cyclopentano-10, 13-dimethyl-phenanthrene, comprising heatingprogesterone with an acylating agent at a temperature of at least about100 C. for a suflicient time to form an enol derivative which isacylated at the enolic hydroxy group.

8. Process for the manufacture of new enol derivatives of 3 ketocyclopentano-10,13-dimethyl-phenanthrene, comprising heatingprogesterone with an aliphatic acylating agent at a temperature of atleast about 100 C. for a sumcient time to form an enol derivative whichis acylated at the enolic hydroxy group.

9. Process for the manufacture of new enol derivatives of 3 ketocyc1opentano-10,l3-dimethyl-phenanthrene, comprising heatingprogesterone with an aliphatic acid anhydride at a temperature of atleast about 100 C. for a suficient time to form an enol derivative whichis acylated at the enolic hydroxy group.

10. Process for the manufacture of new enql derivatives of 3 ketocyclopentano-10,13-dimethyl-phenanthrene, comprising heatingprogesterone with an aliphatic acid anhydride in the presence of ananhydrous salt of such acid at a temperature of at least about 100 C.for a CQHL C O-OW V 15. The enol acetate of testosterone-l'l-propionateof the formula cm OH:

H I O--C0-C:Hl

1O CHz-CO-O-VV 16. The method of producing a more highly nuclearlyunsaturated derivative of cholestenone V which comprises reactingcholestenone with acetic anhydride in the presence 01 an anhydrous saltof acetic acid.

17. The enol esters of unsaturated 3-ketocyclopentano-10,13-dimethylphenanthrene compounds.

LEOPOLD RUZICKA.

WERNER FISCHER.

